公开(公告)号：US20070117811A1

公开(公告)日：2007-05-24

申请号：US11283608

申请日：2005-11-18

申请人： Marcello Leopoldo ,  Francesco Berardi ,  Nicola Colabufo ,  Marialessandra Contino ,  Enza Lacivita ,  Mauro Niso ,  Roberto Perrone ,  Vincenzo Tortorella

发明人： Marcello Leopoldo ,  Francesco Berardi ,  Nicola Colabufo ,  Marialessandra Contino ,  Enza Lacivita ,  Mauro Niso ,  Roberto Perrone ,  Vincenzo Tortorella

IPC分类号： A61K31/496 ,  C07D241/04

CPC分类号： C07D295/15 ,  C07D261/20 ,  C07D263/57

摘要： A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides was prepared and their affinity for serotonin 5-HT7, 5-HT1A, and 5-HT2A receptors was measured using in vitro binding assays. In relation to 5-HT7 receptor affinity, receptor binding studies indicated that: (i) the optimal alkyl chain length was five methylenes; (ii) an unsubstituted 1,2,3,4-tetrahydronaphthalenyl nucleus was selected for further substitutions; and (iii) the substitution pattern of the aryl ring linked to the piperazine ring played a significant role. Several compound with high affinity for 5-HT7 receptors were identified. Among them, 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (28), 4-(2-acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (34), 4-(2-methylthiophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (44), 4-(2-hydroxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (46), 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT7 receptor mediated relaxation of substance P-induced guinea-pig ileum contraction. Compounds 28, 44, and 49 behaved as full agonists, compound 34 as a partial agonist, whereas derivative 46 acted as an antagonist.

摘要翻译： 制备了一系列N-（1,2,3,4-四氢萘-1-基）-4-芳基-1-哌嗪烷基酰胺，并且它们对5-羟色胺5-HT 7 5-HT 使用体外结合测定法测量1A和/或5-HT 2A受体。 关于5-HT 7受体亲和力，受体结合研究表明：（i）最佳烷基链长度为5个亚甲基; （ii）选择未取代的1,2,3,4-四氢萘基核进一步取代; 和（iii）与哌嗪环连接的芳环的取代模式发挥了重要作用。 鉴定了对5-HT 7受体具有高亲和力的几种化合物。 其中，4-（2-甲氧基苯基）-N-（1,2,3,4-四氢萘-1-基）-1-哌嗪己酰胺（28），4-（2-乙酰基苯基）-N-（1,2 ，3,4-四氢萘-1-基）-1-哌嗪己酰胺（34），4-（2-甲硫基苯基）-N-（1,2,3,4-四氢萘-1-基）-1-哌嗪己酰胺（44 ），4-（2-羟基苯基）-N-（1,2,3,4-四氢萘-1-基）-1-哌嗪己酰胺（46），4-（2-甲基苯基）-N-（1,2， 3,4-二氢萘-1-基）-1-哌嗪己酰胺（49）测定5-HT 7受体介导的物质P诱导的豚鼠回肠收缩的松弛。 化合物28,44和49表现为完全激动剂，化合物34作为部分激动剂，而衍生物46用作拮抗剂。

公开(公告)号：US07488730B2

公开(公告)日：2009-02-10

申请号：US11283608

申请日：2005-11-18

申请人： Marcello Leopoldo ,  Francesco Berardi ,  Nicola Antonio Colabufo ,  Marialessandra Contino ,  Enza Lacivita ,  Mauro Niso ,  Roberto Perrone ,  Vincenzo Tortorella

发明人： Marcello Leopoldo ,  Francesco Berardi ,  Nicola Antonio Colabufo ,  Marialessandra Contino ,  Enza Lacivita ,  Mauro Niso ,  Roberto Perrone ,  Vincenzo Tortorella

IPC分类号： A61K31/495 ,  C07D295/15

CPC分类号： C07D295/15 ,  C07D261/20 ,  C07D263/57

摘要： A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides was prepared and their affinity for serotonin 5-HT7, 5-HT1A, and 5-HT2A receptors was measured using in vitro binding assays. In relation to 5-HT7 receptor affinity, receptor binding studies indicated that: (i) the optimal alkyl chain length was five methylenes; (ii) an unsubstituted 1,2,3,4-tetrahydronaphthalenyl nucleus was selected for further substitutions; and (iii) the substitution pattern of the aryl ring linked to the piperazine ring played a significant role. Several compound with high affinity for 5-HT7 receptors were identified. Among them, 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (28), 4-(2-acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (34), 4-(2-methylthiophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (44), 4-(2-hydroxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (46), 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT7 receptor mediated relaxation of substance P-induced guinea-pig ileum contraction. Compounds 28, 44, and 49 behaved as full agonists, compound 34 as a partial agonist, whereas derivative 46 acted as an antagonist.

摘要翻译： 制备了一系列N-（1,2,3,4-四氢萘-1-基）-4-芳基-1-哌嗪烷基酰胺，并测定了它们对5-羟色胺5-HT7,5-HT1A和5-HT2A受体的亲和性 使用体外结合测定。 关于5-HT7受体亲和力，受体结合研究表明：（i）最佳烷基链长度为五个亚甲基; （ii）选择未取代的1,2,3,4-四氢萘基核进一步取代; 和（iii）与哌嗪环连接的芳环的取代模式发挥了重要作用。 鉴定了几种对5-HT7受体具有高亲和力的化合物。 其中，4-（2-甲氧基苯基）-N-（1,2,3,4-四氢萘-1-基）-1-哌嗪己酰胺（28），4-（2-乙酰基苯基）-N-（1,2 ，3,4-四氢萘-1-基）-1-哌嗪己酰胺（34），4-（2-甲硫基苯基）-N-（1,2,3,4-四氢萘-1-基）-1-哌嗪己酰胺（44 ），4-（2-羟基苯基）-N-（1,2,3,4-四氢萘-1-基）-1-哌嗪己酰胺（46），4-（2-甲基苯基）-N-（1,2， 3,4-二氢萘-1-基）-1-哌嗪六酰胺（49）测定了5-HT7受体介导的物质P诱导的豚鼠回肠收缩的松弛。 化合物28,44和49表现为完全激动剂，化合物34作为部分激动剂，而衍生物46用作拮抗剂。